The present invention relates to the mammalian gene 22444, a novel gene associated with the susceptibility of an individual for developing or having a neuropsychiatric disorder such as schizophrenia, schizoaffective disorder or serious mood disorders including bipolar disorder and recurrent unipolar disorder. The present invention encompasses 22444 nucleic acids, recombinant DNA molecules, cloned genes and variants thereof, 22444 gene products, cloning vectors containing mammalian 22444 gene molecules and host cells genetically engineered to express these molecules. The present invention also relates to methods of identifying compounds which modulate expression of 22444 and to the use of these compositions as therapeutic agents in the treatment of these neuropsychiatric disorders. In addition, the present invention relates to methods for diagnostic evaluation, genetic testing and prognosis of neuropsychiatric disorders associated with the 22444 gene. Identification of individuals with mutations in the sequences of the 22444 gene of the present invention is useful as a diagnostic aide for various neuropsychiatric disorders, and in particular schizophrenia, schizoaffective disorders, bipolar disorder and recurrent unipolar disorder.
Historically, schizophrenia (SZ) and bipolar (BP) disorder have been considered as non-overlapping nosological entities, with distinctive clinical characteristics, unique treatment regimens and separate (albeit unknown) etiologies.
The schizophrenic disorders are a group of syndromes manifested by massive disruption of thinking, mood, and overall behavior as well as poor filtering of stimuli. Diagnosis of schizophrenic disorder is currently based upon the presence of a number of behavioral characteristics of at least six months duration including: slowly progressive social withdrawal usually often accompanied by a deterioration in personal care; loss of ego boundaries with the inability to perceive oneself as a separate entity; loose thought associations, often with slowed thinking or overinclusive and rapid shifting from topic to topic; autistic absorption in inner thoughts and frequent sexual or religious preoccupations; auditory hallucinations, often of a derogatory nature; and delusions, frequently of grandiose or persecutory nature. Frequent additional signs include: flat effect and rapidly alternating mood shift irrespective of circumstances; hypersensitivity to environmental stimuli, with a feeling of enhanced sensory awareness; variability or changeable behavior incongruent with the external environment; concrete thinking with the inability to abstract; inappropriate symbolism; impaired concentration worsened by hallucinations and delusions; and depersonalization, wherein one behaves like a detached observer of one""s own actions. Diagnosis of a schizophrenic disorder based upon these behaviors can thus be quite arbitrary and is influenced by sociocultural factors and schools of psychiatric thought. At present, there is no laboratory method for confirmation of a diagnosis of schizophrenia.
Bipolar disorder, also known as manic-depressive illness, involves cycles of mania and depression. Signs and symptoms of mania include: extreme irritability and distractibility; excessive euphoric feelings; a sustained period of behavior that is different from the usual behavior; increased energy activity, restlessness, racing thoughts and rapid talking; decreased need for sleep; unrealistic beliefs in one""s abilities and powers; uncharacteristically poor judgment; increased sexual drive; abuse of drugs, particularly cocaine, alcohol and sleeping medications; obnoxious, provocative or intrusive behavior and denial that anything is wrong. Signs and symptoms of depression include: persistent sad, anxious or empty mood; feeling of hopelessness or pessimism; feeling of guilt, worthlessness or helplessness; loss of interest or pleasure in ordinary activities; decreased energy, a feeling of fatigue or of being xe2x80x9cslowed downxe2x80x9d; difficulty concentrating, remembering and making decisions; restlessness and irritability; sleep disturbances; loss of appetite and weight, or weight gain; chronic pain or other persistent bodily symptoms that are not caused by physical disease; and thoughts of death or suicide. Most people with manic-depressive illness can be helped with treatment. However, manic-depressive illness, which is currently diagnosed by symptoms alone, is often not recognized by the patient, relatives, friends and even physicians. If left untreated, bipolar disorder tends to worsen, and the person experiences episodes of full-fledged mania and clinical depression.
Accordingly, there is a need for better, more definitive diagnostic markers and methods for diagnosing neuropsychiatric disorders including schizophrenia and bipolar disorder and other related disorders.
U.S. Pat. No. 5,866,412 discloses a mammalian gene, fsh15w6, which is associated with bipolar affective disorder in humans. U.S. Pat. No. 5,914,394 discloses a mammalian gene fsh16, which is associated with bipolar affective disorder. U.S. Pat. No. 5,939,316 discloses a mammalian gene, fsh22, which is associated with bipolar affective disorder. U.S. Pat. No. 5,955,355 discloses a mammalian gene, fsh05, which is associated with bipolar affective disorder.
In the present invention, a new mammalian gene associated with neuropsychiatric disorders, referred to herein as 22444, has been identified.
The object of the present invention is to identify genes associated with neuropsychiatric disorders, to provide methods of treating and diagnosing neuropsychiatric disorders, and to provide methods for identifying compounds for use in these therapeutic and diagnostic methods.
In particular, an object of the present invention is to provide a mammalian gene, 22444, which is associated with neuropsychiatric disorders including schizophrenia, schizoaffective disorder and serious mood disorders including bipolar disorder and recurrent unipolar disorder, and nucleic acid sequences, recombinant DNA molecules, cloned genes and variants thereof, of 22444.
Another object of the present invention is to provide mammalian 22444 gene products and antibodies immunospecific for these 22444 gene products, or fragments or variants thereof.
22444 nucleic acid sequences and amino acid sequences are disclosed herein. Accordingly, another object of the present invention is to provide vectors, preferably expression vectors, comprising mammalian 22444, and host cells genetically engineered to express mammalian 22444 gene products.
Another object of the present invention is to provide methods of use of the 22444 gene and 22444 gene products for the diagnostic evaluation, genetic testing and prognosis of a neuropsychiatric disorder. For example, in one embodiment, a method is provided for predicting the susceptibility or predisposition of an individual to having or developing neuropsychiatric disorders including schizophrenia, schizoaffective disorder and serious mood disorders such as bipolar disorder and recurrent unipolar disorder by detecting for the presence or absence of the 22444 gene of gene product or mutations. In this method, the absence of the 22444 gene or gene product or the presence of a mutation thereof is predictive of susceptibility or predisposition of an individual to having or developing one of these neuropsychiatric disorders. In another embodiment, a method is provided for diagnosing neuropsychiatric disorders such as schizophrenia, schizoaffective disorder, and serious mood disorders including bipolar disorder and recurrent unipolar disorder in an individual by analyzing for the presence or absence of the 22444 gene or gene product or a variant thereof in a biological sample obtained from the individual. In this method, the absence of the 22444 gene or gene product or the presence of a variant thereof is indicative of the individual having a neuropsychiatric disorder.
Another object of the present invention is to provide new treatments and methods of identifying new treatments for neuropsychiatric disorders. In one embodiment, these treatments involve modulation of the expression of the mammalian 22444 gene and/or the activity or synthesis of a mammalian 22444 gene product. In another embodiment, treatments involve supplying the mammal with a nucleic acid molecule encoding normal 22444. Methods for identifying new treatments involving modulation of the expression of the 22444 gene and/or the synthesis or activity of 22444 gene products comprise contacting a compound to a cell that expresses a 22444 gene, measuring the level of 22444 gene expression, gene product expression or gene product activity produced by the cell and comparing this level to the level of 22444 gene expression, gene product expression or gene product activity in the cell in the absence of the compound. Compounds which alter the level of 22444 gene expression, gene product expression or gene product activity are thus identified as modulators of 22444 gene expression or gene product synthesis or activity.